Erythropoietin is a cytokine required for red blood cell formation. Erythropoietin receptor expression is not restricted to hematopoietic cells and erythropoietin activity extends beyond blood and includes neural protection and cardiac protection demonstrated in select animal models. We demonstrated erythropoietin receptor expression in skeletal muscle satellite cells but not in mature skeletal muscle fibers. Erythropoietin stimulates myoblast proliferation and modifies expression of MyoD and myogenin transcription factors to delay cell differentiation and fusion to myotubes. Erythropoietin response is lost with down regulation of its receptor after skeletal muscle differentiation. We hypothesized that erythropoietin administration or up regulation of its receptor on myoblasts can contribute to muscle maintenance and/or repair in skeletal muscle. Myoblast transplantation for the treatment of myopathies has the potential to retard or stop muscle degeneration. We examined the protective effect of erythropoietin signaling in myoblasts, and determined that enhanced expression of erythropoietin receptor through gene transfer could be used to enhance erythropoietin response and myoblast survival. A dual-promoter lentiviral vector containing the erythropoietin receptor and a reporter gene was constructed and used to over express erythropoietin receptor in myoblasts. These cells demonstrated a survival advantage in culture under serum starvation conditions and when transplanted in vivo into the mdx mouse model for musclular dystrophy. Transplantation of myoblasts over expressing erythropoietin receptor showed a greater degree of donor cell incorporation into muscle fibers. Transplantation of modified myoblasts also restored dystrophin protein expression in mdx mice at 6 weeks after cell treatment that was further increased with a course of exogenous erythropoietin administration following cell transplantation. Therefore, in this mouse model for muscular dystrophy, enhanced erythropoietin signaling promotes donor cell survival and function in a transplantation setting.